Pharmacokinetics of tildipirosin in beagle dogs

The objective of this study was to investigate the pharmacokinetic profile of tildipirosin (TD) in 24 beagle dogs following intravenous (i.v.) and intramuscular (i.m.) administration, respectively, at 2, 4, and 6 mg/kg. Plasma samples at certain time points (0–14 days) were collected, and the concentrations of drug were quantified by UPLC‐MS/MS. Plasma concentration–time data and relevant parameters were described by noncompartmental through WinNonlin 6.4 software. After single i.m. injection at 2, 4, and 6 mg/kg body weight, mean maximum concentration (C_max) was 412.73 ± 76.01, 1,051 ± 323, and 1,061 ± 352 ng/ml, respectively. Mean time to reach C_max was 0.36 ± 0.2, 0.08 ± 0.00, and 0.13 ± 0.07 hr after i.m. injection at 2, 4, and 6 mg/kg, respectively. The mean value of T_1/2λz for i.m. administration at doses of 2, 4, and 6 mg/kg was 71.39 ± 28.42, 91 .33 ± 50.02, and 96.43 ± 45.02 hr, respectively. The mean residence times were 63.81 ± 10.96, 35.83 ± 15.13, and 38.18 ± 16.77 hr for doses of 2, 4, and 6 mg/kg, respectively. These pharmacokinetic characteristics after i.m. administration indicated that TD could be rapidly distributed into tissues on account of the high lipid solubility and then released into plasma. In addition, the absolute bioavailability of 2 mg/kg after i.m. injection was 112%. No adverse effects were observed after i.v. and i.m. administration.     

Pharmacokinetics of single‐dose sildenafil administered orally in clinically healthy dogs: Effect of feeding and dose proportionality

Basic information related to the pharmacokinetics of sildenafil in dogs is scarce. This study aimed to describe the pharmacokinetic properties of oral sildenafil and determine the effect of feeding and dose proportionality. The effect of feeding on pharmacokinetics of sildenafil (1 mg/kg) was investigated using a crossover study with six dogs. In addition, the dose proportionality of sildenafil ranging 1–4 mg/kg was evaluated using five dogs in the fasted states. The plasma concentrations of sildenafil were determined using high‐performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil administrations were well tolerated in all studies. Feeding reduced the area under the curve extrapolated to infinity (AUC_inf) and the maximum plasma concentration (C_max) significantly. The elimination half‐life (T_1/2) did not differ between the fasted and the fed states. For dose proportionality, nonproportional increases in AUC_inf and C_max at 1–4 mg/kg doses were detected by a power model analysis.     

Plasma lactate measurements in healthy beagle dogs

Plasma lactate concentrations were determined in venous blood samples collected from 60 healthy Beagles aged 5 to 9 months. The range of values (0.42 to 3.58 mmol/L) obtained with an enzymatic method in the present study was similar to values reported in smaller studies with the colorimetric procedures.     

美洛昔康片剂在比格犬内的药代动力学及生物利用度研究

本研究以0.1 mg/kg体重的剂量研究美洛昔康片在比格犬中的药代动力学和生物利用度。HPLC分析血浆中的药物浓度,WinNonlin 6.4非房室模型计算药动学参数。比格犬内服美洛昔康片后测得0~48 h美洛昔康的T1/2、Cmax、Tmax和AUC0-t分别为14.55 ± 2.18 h、296.16 ± 74.15 ng·mL-1、6.0 ± 0.00 h和6356.79 ± 1089.78 ng·h·mL-1;比格犬静脉注射美洛昔康溶液后,测得0~48 h美洛昔康的T1/2和AUC0-t分别为11.54 ± 4.18 h和5510.68 ± 1075.29 ng·h·mL-1。内服美洛昔康片剂的绝对生物利用度为115.35%。美洛昔康片在比格犬体内消除速率较慢,消除半衰期较长,在体内滞留时间较长,绝对生物利用度高,药物在体内作用时间较长等药动学特征。     

Pharmacokinetics of a controlled‐release liposome‐encapsulated hydromorphone administered to healthy dogs

The purpose of the study was to assess the pharmacokinetics of liposome‐encapsulated (DPPC‐C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14–28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC‐C formulation (half‐life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half‐life of hydromorphone after SC administration of DPPC‐C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (C_MAX/D) ranged between 19.41–24.96 ng/mL occurring at 0.18–0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6–72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC‐C hydromorphone. Liposome‐encapsulated hydromorphone (DPPC‐C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.     

A toxicity study of low‐dose rate half‐body irradiation and chemotherapy in dogs with lymphoma

Thirteen dogs with previously untreated multicentric lymphoma were enrolled in a prospective study investigating the effects of low‐dose rate total body irradiation (TBI) and chemotherapy. Dogs received either 6 or 8 Gy TBI in half‐body fractions, 2 weeks apart. Toxicity consisted of mild to moderate haematological and gastrointestinal (GI) signs. One dog died from treatment complications. Anorexia was noted independent of dose. Haematological toxicity was more common and more severe after 8 Gy treatment. GI toxicity was more likely postcaudal half‐body irradiation with 8 Gy. Other than leukotrichia, late effects from radiation were not observed. Results indicated that haematological and nonhaematological toxicity was dose dependent. However, the protocol was well tolerated and treatment intensification using a 2‐week inter‐radiation interval was possible in all dogs treated with 6 Gy. Preliminary survival data for these dogs were very encouraging, providing a strong rationale to analyse the efficacy of low‐dose rate irradiation (LDRI) in canine lymphoma.     

Pharmacokinetics and ex‐vivo pharmacodynamics of cefquinome against Klebsiella pneumonia in healthy dogs

A two‐period cross‐over study was carried to investigate the pharmacokinetics (PK) and ex‐vivo pharmacodynamics (PD) of cefquinome when administrated intravenously (IV) and intramuscularly (IM) in seven healthy dogs at a dose of 2 mg/kg of body weight. Serum concentrations were determined by HPLC‐MS/MS assay and cefquinome concentration vs. time data after IV and IM were best fit to a two‐compartment open model. Cefquinome mean values of area under concentration–time curve (AUC) were 5.15 μg·h/mL for IV dose and 4.59 μg·h/mL for IM dose. Distribution half‐lives and elimination half‐lives after IV dose and IM dose were 0.27 and 0.44 h, 1.53 and 1.94 h, respectively. Values of total body clearance (Cl_B) and volume of distribution at steady‐state (V_ss) were 0.49 L·kg/h and 0.81 L/kg, respectively. After IM dose, C_max was 2.53 μg/mL and the bioavailability was 89.13%. For PD profile, the determined MIC and MBC values against K. pneumonia were 0.030 and 0.060 μg/mL in MHB and 0.032 and 0.064 μg/mL in serum. The ex vivo time‐kill curves also were established in serum. In conjunction with the data on MIC, MBC values and the ex vivo bactericidal activity in serum, the present results allowed prediction that a single cefquinome dosage of 2 mg/kg may be effective in dogs against K. pneumonia infection.     

Pharmacokinetics of hydromorphone hydrochloride in healthy dogs

ObjectiveTo assess the pharmacokinetics of hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs.Study designRandomized experimental trial.AnimalsSeven healthy male neutered Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg.MethodsThe study was a randomized Latin square block design. Dogs were randomly assigned to receive hydromorphone hydrochloride 0.1 mg kg⁻¹ or 0.5 mg kg⁻¹ IV (n = 4 dogs) or 0.1 mg kg⁻¹ (n = 6) or 0.5 mg kg⁻¹ (n = 5) SC on separate occasions with a minimum 14-day washout between experiments. Blood was sampled via a vascular access port at serial intervals after drug administration. Serum was analyzed by mass spectrometry. Pharmacokinetic parameters were determined with computer software.ResultsSerum concentrations of hydromorphone decreased quickly after both routes of administration of either dose. The serum half-life, clearance, and volume of distribution after IV hydromorphone at 0.1 mg kg⁻¹ were 0.57 hours (geometric mean), 106.28 mL minute⁻¹ kg⁻¹, and 5.35 L kg⁻¹, and at 0.5 mg kg⁻¹ were 1.00 hour, 60.30 mL minute⁻¹ kg⁻¹, and 5.23 L kg⁻¹, respectively. The serum half-life after SC hydromorphone at 0.1 mg kg⁻¹ and 0.5 mg kg⁻¹ was 0.66 hours and 1.11 hours, respectively.Conclusions and clinical relevanceHydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg⁻¹ IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg⁻¹ hour⁻¹ are suggested for future studies to assess the analgesic effect of hydromorphone.     

Furosemide for prevention of cyclophosphamide‐associated sterile haemorrhagic cystitis in dogs receiving metronomic low‐dose oral cyclophosphamide

Sterile haemorrhagic cystitis (SHC) is a known risk of cyclophosphamide treatment. Diuresis using furosemide is effective in canines when maximally tolerated dosed cyclophosphamide is administered. This retrospective study aimed to determine whether orally administered furosemide decreased the incidence of SHC. Secondary aims were to identify predisposing factors for SHC. One‐hundred and fifteen dogs treated with metronomic cyclophosphamide were analysed retrospectively. Populations were not randomized. 25 dogs (21.7%) developed SHC. Furosemide administration significantly reduced the likelihood of SHC development (P = 0.010, where SHC was diagnosed in 30.3% of dogs administered cyclophosphamide without furosemide, and 10.2% of dogs administered cyclophosphamide with furosemide). Age, gender, breed, bodyweight, number of cyclophosphamide treatments, piroxicam use and previous or pre‐existing disease were not found to be associated with SHC development. This study demonstrates furosemide is effective in the prevention of SHC and its use may be considered when implementing metronomic cyclophosphamide therapy.     

Influence of age on bronchoscopic findings in healthy beagle dogs

The aims of this study were to evaluate the effect of age on bronchoscopic features and bronchoalveolar lavage fluid (BALF) cellularity in dogs. Thirty healthy beagle dogs from three age groups were included: young dogs (10 months to 4.5 years of age; n = 8), middle-aged dogs (5–8 years old; n = 13) and older dogs (>8 years; n = 9). Haematology, thoracic radiography, bronchoscopy and bronchoalveolar lavage were performed; bronchoscopic findings were scored and BALF total and differential cell counts were determined. The total bronchoscopic score was higher in older dogs; these dogs had more irregular bronchial mucosa, more prominent mucosal vessels and bronchiectasis. Younger dogs had a higher percentage of neutrophils in BALF compared with middle-aged and old dogs and a higher percentage of lymphocytes in BALF compared with middle-aged dogs. The results show that age has an effect on bronchoscopic features of airways and the composition of BALF in the dog.     

Pharmacokinetics of ammonium sulfate gradient loaded liposome‐encapsulated oxymorphone and hydromorphone in healthy dogs

ObjectiveTo evaluate the pharmacokinetics, in dogs, of liposome–encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG).AnimalsFour healthy purpose–bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg.Study designRandomized cross–over design.MethodsEach dog was given either 4.0 mg kg^?1 of ASG–oxymorphone or 8.0 mg kg^?1 of ASG–hydromorphone SC on separate occasions with a 3–month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC–MS and pharmacokinetic parameters were calculated using commercial software and non–compartmental methods.ResultsSerum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. C_max for ASG–oxymorphone was 7.5 ng mL^?1; C_max for ASG–hydromorphone was 5.7 ng mL^?1.Conclusions and clinical relevanceOxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs.     

Intradermal and serological testing for mites in healthy beagle dogs

Background – Intradermal testing (IDT) is widely used in veterinary medicine to select allergens for immunotherapy. The recommended concentration for mites is 250 protein nitrogen units (PNU)/mL. It is not known whether healthy dogs responding to this concentration have asymptomatic sensitization or irritation. Furthermore, interbatch and intersupplier variability of allergens has not been fully addressed. Hypothesis/Objectives – The incidence of positive IDTs in healthy beagles was recorded and the value of combining these results with serology to differentiate between asymptomatic sensitization and irritancy evaluated. Additionally, the interbatch and intersupplier variability of allergens was assessed. Animals – Seventeen healthy laboratory beagles with no history or clinical signs of canine atopic dermatitis were used. Methods – Intradermal tests were performed with four mite allergens from two suppliers (varying batches). An initial IDT at 250 PNU/mL was used to determine whether decreasing or increasing test concentrations were used in the subsequent titration IDTs. Additionally, two IgE ELISA tests from different manufacturers were performed. Results – Seven of 17 dogs showed IDT reactions at 250 PNU/mL. There were highly significant allergen interbatch and significant intersupplier correlations and agreement. The associations between the IDT reactions and the IgE serologies statistically identified two groups of dogs: one with positive serology and IDT reactions at 250 PNU/mL; and another with negative serology and IDT reactions. Conclusions and clinical importance – Our results suggest that dogs that have IDT reactions and positive serology are asymptomatically sensitized, while dogs that react at higher allergen concentrations, but have negative serology, do so as a result of irritant reactions.     

Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis

Meropenem, a second carbapenem antimicrobial agent with a broad spectrum of activity, is used to treat sepsis and resistant‐bacterial infections in veterinary medicine. The objective of this study was to identify the pharmacokinetics of meropenem in dogs receiving intermittent hemodialysis (IHD) and to determine the proper dosing in renal failure patients receiving IHD. Five healthy beagle dogs were given a single i.v. dose of 24 mg/kg of meropenem and received IHD. The blood flow rate, dialysate flow, and ultrafiltration rate were maintained at 40 mL/min, 300 mL/min, and 40 mL/h, respectively. Blood samples were collected for 24 h from the jugular vein and from the extracorporeal arterial and venous line. Urine samples and dialysate were also collected. The concentrations of meropenem were assayed using HPLC/MS/MS determination. The peak plasma concentration was 116 ± 37 μg/mL at 15 min. The systemic clearance was 347 ± 117 mL/h/kg, and the steady‐state volume of distribution was 223 ± 67 mL/kg. Dialysis clearance was 71.1 ± 34.3 mL/h/kg, and the extraction ratio by hemodialysis was 0.455 ± 0.150. The half‐life (T_1/2) in dogs with IHD decreased compared with those without IHD, and the reduction in T_1/2 was greater in renal failure patients than in normal patients. Sixty‐nine percent and 21% of the administered drug were recovered by urine and dialysate in the unchanged form, respectively. In conclusion, additional dosing of 24 mg/kg of meropenem after dialysis could be necessary according to the residual renal function of the patient based on the simulated data.     

Pharmacokinetics and selected pharmacodynamics of romifidine following low‐dose intravenous administration in combination with exercise to quarter horses

Romifidine is an alpha‐2 adrenergic agonist used for sedation and analgesia in horses. As it is a prohibited substance, its purported use at low doses in performance horses necessitates further study. The primary goal of the study reported here was to describe the serum concentrations and pharmacokinetics of romifidine following low‐dose administration immediately prior to exercise, utilizing a highly sensitive liquid chromatography–tandem mass spectrometry assay that is currently employed in many drug testing laboratories. An additional objective was to describe changes in heart rate and rhythm following intravenous administration of romifidine followed by exercise. Eight adult Quarter Horses received a single intravenous dose of 5 mg (0.01 mg/kg) romifidine followed by 1 h of exercise. Blood samples were collected and drug concentrations measured at time 0 and at various times up to 72 h. Mean ± SD systemic clearance, steady‐state volume of distribution and terminal elimination half‐life were 34.1 ± 6.06 mL/min/kg and 4.89 ± 1.31 L/kg and 3.09 ± 1.18 h, respectively. Romifidine serum concentrations fell below the LOQ (0.01 ng/mL) and the LOD (0.005 ng/mL) by 24 h postadministration. Heart rate and rhythm appeared unaffected when a low dose of romifidine was administered immediately prior to exercise.